Fabry disease is an X-linked lysosomal disorder that leads to excessive deposition of neutral glycosphingolipids in the vascular endothelium of several organs in the body and epithelial and smooth muscle cells. Progressive endothelial accumulation of glycosphingolipids accounts for the associated clinical abnormalities of skin, eye, kidney, heart, brain, and peripheral nervous system.
When young patients present with signs and symptoms of a stroke, along with a history of skin lesions, renal insufficiency or failure, and heart attacks, Fabry disease is a consideration. Research suggests that Fabry mutations may be more frequent than previously thought in cryptogenic stroke patients, but these patients invariably had other signs of Fabry disease, including proteinuria and acroparesthesias. The diagnosis of Fabry disease has considerable implications regarding treatment, management, and counseling. Specifically, physicians may be alert to the involvement of other organs besides those of the CNS and thus make early intervention possible. With early identification, counseling and prenatal diagnosis may be offered to family members.
Deficiency of alpha-galactosidase A activity leads to lysosomal accumulation of glycosphingolipids, predominantly the cerebroside trihexosides. Diffuse abnormal accumulation of glycosphingolipids occurs in all tissues.
Accumulation of glycosphingolipids produces swelling and proliferation of endothelial cells. Abnormal reactivity of endothelial cells with changes in blood flow in the brain and in peripheral vessels has been documented on magnetic resonance imaging (MRI), positron emission tomography (PET), transcranial Doppler imaging (TCD), and plethysmography.
Disturbances in intraluminal pressure and angioarchitecture are thought to lead to dilatation, angiectasia, and dolichoectasia. The vertebrobasilar arteries appear particularly susceptible to dilatational arteriopathy. Small penetrating arteries frequently become narrowed and occluded. Cerebral infarcts result from direct vascular occlusion or stretching and from distention of branches of the dolichoectatic parent vessels.
Decreased levels of thrombomodulin (TM) and increased plasminogen activator inhibitor (PAI) were found in Fabry disease patients thus suggesting that a prothrombotic state may be one cause of stroke in these patients.
The precise cause of increased incidence of stroke is not established. Findings that could contribute to this increased risk include abnormal nitric oxide and non-nitric oxide dependent endothelial dilation and abnormal endothelial nitric oxide synthase (eNOS) activity leading to aberrant vascular functioning. Paradoxical hyperperfusion is seen in strokelike lesions whose significance is not known.
Nonischemic compressive complications of dolichoectatic intracranial arteries include hydrocephalus, optic atrophy, trigeminal neuralgia, and cranial nerve palsies.
The prevalence of Fabry disease has been previously estimated to be 1 per 40,000. Most of the patients are Caucasian, but it is also found in African Americans and those of Hispanic or Asian descent.
A prospective multicenter study of cryptogenic strokes from Germany suggests that the prevalence could be as high as 1.2%.[1] This would mean that the prevalence rate is higher than mutations of factor V Leiden.
Because Fabry disease affects several organ systems, morbidity and mortality are related to the combined effects of renal failure, heart failure, and stroke.
Patients with Fabry disease seek care from a variety of specialists, usually because of the involvement of a number of organ systems. Hypertension occurs with increased frequency in patients with Fabry disease because of progressive renal impairment. Other traditional risk factors for stroke, such as diabetes, hypercholesterolemia, and smoking, may or may not be present in these patients. Fabry disease must be high on the list of differential diagnoses when a young man presents with signs and symptoms of stroke, along with other characteristic lesions, as described below.
The diffuse involvement of different organ systems leads to a number of abnormalities that can be discovered on physical examination.
Lipid-laden cells have been described in endothelial cells, epithelial cells, muscle fibers, and ganglion cells.
Antiplatelet agents are used for secondary stroke prevention. Anticoagulation with warfarin is prescribed when a cardioembolic stroke is suspected. Painful neuropathies can be treated with a variety of medications, including carbamazepine or phenytoin.
Two enzymes, agalsidase-alpha (Replagal) and agalsidase-beta (Fabrazyme), reportedly help in normalizing renal function, cardiac function, and cerebrovascular flow. Whether therapy with these enzymes changes the natural history of strokes attributable to Fabry disease is unclear.
These agents inhibit the cyclooxygenase system, decreasing the level of thromboxane A2, which is a potent platelet activator.
Clinical Context: Inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2.
Clinical Context: Second-line antiplatelet therapy for patients who cannot tolerate or do not respond to aspirin therapy.
Clinical Context: Selectively inhibits ADP binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, inhibiting platelet aggregation.
Clinical Context: To complement usual warfarin or aspirin therapy. Platelet adhesion inhibitor, possibly inhibits RBC uptake of adenosine, itself an inhibitor of platelet reactivity. May inhibit phosphodiesterase activity, leading to increased cyclic-3', 5'-AMP in platelets and formation of potent platelet activator thromboxane A2.
These agents are used in the treatment of clinically evident intravascular thrombosis.
Clinical Context: Interferes with hepatic synthesis of vitamin K-dependent coagulation factors. For prophylaxis and treatment of deep venous thrombosis, pulmonary embolism, and thromboembolic disorders.
These agents are the recombinant form of the enzyme alpha-galactosidase and beta-galactosidase-A.
Clinical Context: Recombinant form of the human enzyme alpha-galactosidase A, levels of which are deficient in Fabry disease. Data from clinical trials show a decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduced or relief from neuropathic pain. Following enzyme replacement, the long-term use of neuropathic pain medication has been reduced.
Manufactured by Transkaryotic Therapies, Inc (Cambridge, Mass) and is based on activation of the human GLA gene expression in human (skin) fibroblasts.
Clinical Context: Recombinant form of the human enzyme alpha-galactosidase A, levels of which are deficient in Fabry disease. Data from clinical trials show a decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduced or relief from neuropathic pain. Following enzyme replacement, the long-term use of neuropathic pain medication has been reduced.
Manufactured by Genzyme Corporation (Cambridge, Mass) and is based on expression of the human GLA gene in CHO cells.